Project Summary/Abstract Detailed neuropathological investigations suggest that nearly all adults >50 years of age have pathological evidence of neurofibrillary tau tangles (NFTs) and rarely (<1%) are lacking any form of molecular pathology. As individuals age there is also an increased risk of NFTs co-occurring with amyloid-beta plaques (A?) consistent with Alzheimer's disease (AD) molecular pathology. However, the recently coined term primary age-related tauopathy (PART) describes the presence of NFTs in a subset of older adults in an identical distribution to AD but with absent-to-minimal A? pathology. In contrast, there is increasing evidence that AD neuropathology can additionally be accompanied by alpha-synuclein (ASYN), the hallmark of Parkinson's disease (PD), and/or tar- DNA binding protein (TDP-43), the hallmark molecular basis of frontotemporal degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To date, the mechanisms underlying the age-related neuropathological spectrum of NFTs-only in PART and inclusions of ASYN and TDP-43 pathology in AD are unclear. In this proposal we introduce the ?resistance hypothesis? that suggests that some individuals have neuro-protective resources that limit their accumulation of A? in PART and their accumulation of ASYN and/or TDP-43 pathology in AD. We also consider the co-occurrence of molecular pathologies in related disorders, including ALS and PD. The overarching goal of this proposal is to test the hypothesis that genetic and biological aging mechanisms provide resistance to age-related molecular pathologies and to uncover mechanisms supporting resistance in this aging population. To achieve this goal we will analyze neuropathological and genetic data in >1160 well-characterized autopsy-confirmed samples from our NIA-funded Alzheimer's Disease Center (ADC) and related neuropathology cores, as we as supplement these analyses with similar public datasets. We propose 3 specific aims: (1) Determine whether resistance to age-related molecular pathology is associated with reduced severity and admixture of pathologies; (2) Investigate whether ?protective? alleles of single nucleotide polymorphisms associate with resistance against molecular pathology; (3) Evaluate whether efficient ?biological? aging of regional brain tissue is protective against molecular pathology, including a DNA measure of single telomere length analysis (STELA), a transcriptional measure of p16 cyclin-dependent kinase inhibitor expression, and an epigenetic measure of DNA methylation (mDNA). Together, by investigating mechanisms of resistance to molecular pathology in aging, this proposal addresses a NIH priority to better understand the common mechanisms and interactions among neurodegenerative diseases. By better understanding the genetic factors that contribute to resistance of molecular pathology we aim to identify candidate pathways for treatment approaches to prevent accumulation of proteinopathies. A significant proportion of the aging neurodegenerative disease population has mixed pathology and this research will provide a template for developing treatment approaches that address this important issue of heterogeneity.